Attenuation of renal fibrosis after unilateral ureteral obstruction in mice lacking the N-type calcium channel

• Published in: PloS one 2019-10, Vol.14 (10), p.e0223496-e0223496
• Main Authors: Mishima, Keiichiro, Nakasatomi, Masao, Takahashi, Shunsuke, Ikeuchi, Hidekazu, Sakairi, Toru, Kaneko, Yoriaki, Hiromura, Keiju, Nojima, Yoshihisa, Maeshima, Akito
• Format: Article
• Language: English
• Subjects: Actins - genetics; Actins - metabolism; Animal experimentation; Animals; Attenuation; Biology and Life Sciences; Blood pressure; Blood vessels; Calcium; Calcium channels; Calcium channels (N-type); Calcium channels (voltage-gated); Calcium Channels, N-Type - deficiency; Calcium Channels, N-Type - genetics; Calcium ions; Cell Hypoxia; Collagen; Collagen (type I); Collagen Type I - genetics; Collagen Type I - metabolism; Complications and side effects; Diabetes; Fibrosis; Gene expression; Heart rate; House mouse; Hydroxylase; Hydroxylases; Hypertension; Hypoxia; Ischemia; Kidney - metabolism; Kidney - pathology; Kidney diseases; Kidney Diseases - etiology; Kidney Diseases - genetics; Kidney Diseases - metabolism; Kidneys; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Nephrology; Nerves; Nervous system; Neurons; Neurons - metabolism; Novels; Phenols (Class of compounds); Prevention; Quantitative analysis; Renal function; Renal nerve; Renal plexus; Research and Analysis Methods; Rheumatology; Risk factors; Rodents; Sympathetic nerves; Tubules; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; University graduates; Ureteral obstruction; Ureteral Obstruction - complications; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0223496

The N-type Ca2+ channel (Cav2.2) is distributed in sympathetic nerves that innervate the tubules, the vessels, and the juxtaglomerular granular cells of the kidney. However, the role of N-type Ca2+ channels in renal disease remains unknown. To address this issue, Cav2.2 knockout mice were utilized. Immunoreactive Cav2.2 was undetectable in normal kidneys of C57BL/6N mice, but it became positive in the interstitial S100-positive nerve fibers after unilateral ureteral obstruction (UUO). There were no significant differences in mean blood pressure, heart rate, and renal function between wild-type littermates and Cav2.2-knockout mice at baseline, as well as after UUO. Cav2.2 deficiency significantly reduced the EVG-positive fibrotic area, alpha-SMA expression, the production of type I collagen, and the hypoxic area in the obstructed kidneys. The expression of tyrosine hydroxylase, a marker for sympathetic neurons, was significantly increased in the obstructed kidneys of wild-type mice, but not in Cav2.2-knockout mice. These data suggest that increased Cav2.2 is implicated in renal nerve activation leading to the progression of renal fibrosis. Blockade of Cav2.2 might be a novel therapeutic approach for preventing renal fibrosis.